N-dialkyl alkoxynaphthamidines



Patented Dec. 20, 1949 UN I TED STAT ES 2,491,473 N-DIALKYL ALKOXYNAPHTHAMIDINES Richard Baltzly, New York, and Emil 1. "Yonkers, N. Y., assignors t Burroughs Wellc0me-& Co. (U. S. A.) Inc., Tilckahoe,N."Y., a corporation of New'York No Drawing. Application November 16, 1948, Serial No. 60,418

9 Claims. (01. zen-#564) 'The present invention relates to a new group of chemical compoundsandmore particularly to a new type 'of substituted amidines which have beenfound to possess outstanding properties as localanesthetics inveterinary medicine, especialiy for'surface anesthesia. At least some of the new compounds are also believed to be suitableforapplication in human medicine, but at present the clinical tests on these compounds have not been completed.

The'new compounds are readily prepared in excellent yield by the methods disclosed in our co-pending -U. S. application Serial Number 700,366, of which the present application is a continuation in part.

The physiologically active compounds according to the present-invention, may be graphically represented by the formula:

URI!

in which R and 'R' are alkyl. groups containing together from' four to ten'ca'rbon atoms, R." is a lower alkyl' group containing one to four carbon atoms.

As bases these amidines are only moderately stable and are insoluble or sparingly soluble in water. They are therefore best handled as their salts, which have very great stability and are readily soluble in water. The acid used to form the salts contributes nothing to the physiological activity of the substances and is not of a critical nature, provided it is not itself highly toxic. Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or organic acids such as malic acid, 'succinic acid, lactic acid or the like may be employed'and-an'y of these may'offer advantages in individual cases but hitherto no other acid has been found'preferable to hydrochloric acid. We therefore consider all non-toxic acids to be equivalent for this purpose and regard salts of this family of amidines with any such acid to be comprehended in the invention.

As an indication of the potency of these substances, when tested on the cornea of a guinea pig, 4-meth6ky N,;N-di-n butyl alpha naphthamidine is foundto be 2 times as potent as cocaine while 4-methoxy N.N di-secbutyl-alphanapthamidine is about 50 times as powerful. The

toxicities, on the otherhand, are only 2-3 times as great making the substances far' more eificient and safe in application. "When the size of the a kyl groups attached to the" amidine nitrogen atom is increased the toxicity becomes greater and there is considerable local irritation, the di-" 2 n-hexyl compound being unsuitable for use for that reason. Decrease in'thesize of these alkyl groups beyond a certain limit corresponds to a marked diminution in potency.

The following list of compounds, though not exhaustive, is believed to be representative of the physiologically active substituted amidines according to the present invention:

1. N methyl N isopropyl 4 -methoxy-alphanaphthamidine.

2 N-methyl-N-n-butyl-4-methoxy-alpha-naphthamidine.

3. N-methyl-N-n-nonyl-4-methoxy-alpha-naphthamidine. A

4. N-ethyl-N-n Qctyl-Q-m'ethOXy alpha -naphthamidine.

5. N ,N di-n-propyl-4 methoxy-alpha-naphthamidine.

6. N,N -di-isopropyl-4-lnethoi y=alpha naphthamidine.

'7. N n propyl -N n amyl-i methoxy-alphanaphthamidine.

8. N,N di n-butyl-4-m,ethoxy-alpha-naphthamidine.

9. N ,N di isobutyl-4-methoxy-alpha-naphthamidine; I

10. N,N-di-sec-butyl-4-methoxy-alpha-naphthamidine.

11. N,N di -n-amyl-4 methoxy-alpha-naphthamidine.

12. N,N di-isoamyl-4-methoxy-alpha-naphthamidine. V I g 13.; N,N-diethyl-4-ethoxy-alpha-naphthamidine.

14. N-ethyl -N n-propyl-4-ethoxy-alpha-naph-:

'thamidine,

15, N-ethyl-N-n-amyl-4-ethoxy-alphamaphthamidine.

16 N-ethyl-N-isobutyl 4 ethoxy -alpha-naphtharnidine.

17.- N,N-di-n-propyl-4-ethoxy-alpha-naphtham:l

dine.

18'. N ,N-di-lsopropyll-ethoxy-alpha naphthahalomagn'esium dialk'ylamide of the formula RRNMgY (in which Y is a halogen atom) upon a l-alkoxy-alpha-naphthonitri1e. The product initially formed is the halomagnesium derivative of the amidine. When the reaction mixture is hydrolyzed, as by iced ammonium chloride solution, the halomagnesium radical is replaced by hydrogen, liberating the amidine which can be separated by procedures described below and transformed to suitable salts for easier manipulation and greater stability.

The nitriles employed in the preferred synthesis are readily obtained by the following series of reactions:

in pyridine ORI! Methods for the preparation of the substituted amidines according to the present invention are illustratively exemplified in the following examples which, however, are not intended to limit the scope of the invention:

Example 1 .N,Ndi-n-propyl-4-methoa:y-

alpha-naphthamidine To a solution of ethyl magnesium bromide in ether, prepared from 2.5 g. of magnesium and 10.8 g. of ethyl bromide was added gradually 10.1 g.' of di-n-propyl amine and the solution was refluxed thirty minutes after the addition had been completed. There was then added slowly 9 g. of 4-methoxy-alpha-naphthonitrile dissolved in ether and the whole was refluxed four hours. The reaction mixture was poured into iced ammonium chloride solution and the ethereal layer was separated. The aqueous layer was basified further with aqueous alkali, extracted with ether and the extract combined with the previous ethereal layer. These ethereal layers were washed with dilute sodium hydroxide solution, filtered from a little precipitated magnesium hydroxide and dried over potassium carbonate. The dry ethereal solution was evaporated on the steam bath, finally in vacuo to remove traces of secondary amine. The residue which was a brownish oil Weighing 12.5 g., was dissolved in absolute ethanol containing two g. of hydrogen chloride and ether was added to induce crystallization. The hydrochloride, after recrystallization from ethanol-ether mixtures, melted at about 226 C. with decomposition.

Example 2.-N,N-di-isopropyl-4-meth0wyaZpha-naphthamidine A Grignard reagent was prepared from g. of

magnesium and 21.6 g. of ethyl bromide and was reacted with 21.8 g. of di-isopropylamine, the

solution being refluxed thirty minutes after addition was complete. Ten g. of 4-methoxy-alpha- 'naphthonitrile was added gradually and the resolution was basified with alkali. The amidine base was taken into ether, dried over potassium carbonate and the dry solution was evaporated in vacuo (on the steam bath) The residue, which weighed about 14 g. (calculated 15.5 g.) solidified on standing. It was recrystallized from etherhexane mixture and transformed to the hydrochloride which melts at 241 C. The hydrochloride can be crystallized from ethanol-ether mixtures.

Example 3.-N,N-di-n-butyl-4-methoxyalpha-naphthamidine One-fifth mole (26 g.) of di-n-butylamine was added gradually to a solution of ethylmagnesium bromide prepared from 5 g. of magnesium and 22 g. of ethyl bromide. After addition of secondary amine was complete the solution was refluxed thirty minutes and a solution of 18.3 g. (0.1 mole) of 4-methoxy-alpha-naphthonitrile in cc. of absolute ether was admitted slowly. When all the nitrile was in, the solution was refluxed three hours and poured into iced ammonium chloride solution. A magnesium derivative of the amidine precipitated as a solid at this point and was filtered off, thereby effecting separation from secondary amine. On treatment with alkali and extraction with ether the amidine passed into the ethereal layer which was dried over potassium carbonate and evaporated. The amiding base was a light yellow oil weighing 26 g. (83.5% yield). The oil was dissolved in 50 cc. of absolute ethanol, and 10 g. of 35% ethanolic hydrogen chloride (wt/wt.) was added. The solution was diluted with absolute ether to the point of incipient turbidity, whereupon the hydrochloride separated on'scratching. This salt melted at 230 (dec.), when first obtained and subsequent recrystallizations from ethanol-ether mixtures did not raise the melting point.

Similarly, bromomagnesium di-n-butylamide reacted with 4-ethoxyand 4-n-butoxy-alphanaphth-onitriles to yield N,Ndi-n-butyl-4-ethoxynaphthamidines whose hydrochlorides melt at 234-5" C. and 219 C. respectively.

Example 4.-N,N-di-isobutyl-4-methoxyalpha-naphthwmidine Example 5.-N,N-di-sec-but1/l-4-methoxy-alphanaphthamidine A solution of bromomagnesium di-sec-butylamide was prepared by the addition of 14 g. of disec-butylamine to a solution of ethyl magnesium bromide formed from 2.5 g. of magnesium and 10.8 g. of ethyl bromide. After the usual thirty minutes refluxing 9 g. of 4-methoxy-alpha-naphthonitrile dissolved in benzene was added and refiuxing was continued for 4 hours. Hydrolysis and separation of amidine base was as described in Example 2. The base was transformed to the hydrochloride which melted initially at 237 C.

and N,N-di-n-butyl-4-nbutoxy-alphagive N,N-di-sec-butyl-4-n-butoxy-alpha-naphthamidine.

Example 6.-N,N-di-iso-amyl-4-methoxy-alphanaphthamidine Bromomagnesium di-iso-amyl amide, prepared by the procedures of the previous examples, was reacted with 4-methoxy-alpha-naphthonitrile to form N,N-di-iso-amyl-4-methoxy-alpha-naphthamidine. Since the secondary amine in this case is relatively involatile the ethereal solution of the amidine base was evaporated at 120 C. in vacuo instead of on a steam bath. The residual base weighed 15.5 g. (91%) and formed a hydrochloride that melted initially at 207 and at 208 after recrystallization from ethanol-ether mixture. The base must therefore have been substantially pure as isolated, although not crystalline.

Similarly, N,N-di-n-amyl-4-methoxy-alphanaphthamidine (M. P. of hydrochloride, 209 C.) was obtained from 4-methoxy-alpha-naphthonitrile and bromomagnesium di-n-amyl amide.

By the application of the methods above described N-n-propyl-N-n-amyl-4-methoxy-alphanaphthamidine, and N-methyl-N-n-nonyl- -lmethoxy-alpha-naphthamidine were also prepared from the appropriate bromomagnesium dialkylamides and 4-alkoxy-alpha-naphthonitriles.

We claim:

1. Substituted amidines of the type represented by the formula in which R and R are alkyl groups containing together from four to ten carbon atoms, and R" is a lower alkyl group containing one to four carbon atoms, and the water soluble salts of these amidines with non-toxic acids.

2. Substituted amidines of the type represented by the formula HN=O 0 CH3 and the water soluble salts of these amidines with non-toxic acids.

3. Substituted amidines of the type represented by the formula HN=CN UC2H5 and the water soluble salts of these amidines with non-toxic acids.

4. N,N di n butyl 4 methoxy alpha naphthamidine and its water soluble salts with non-toxic acids.

5. N,N di n butyl 4 methoxy alpha naphthamidine hydrochloride.

6. N,N, di sec butyl 4 methoxy alpha naphthamidine and its water soluble salts with non-toxic acids.

7. N,N di sec butyl 4 methoxy alpha naphthamidine hydrochloride.

8. N,N di n butyl 4 ethoxy alpha naphthamidine and it water soluble salts with non-toxic acids.

9. N,N di n butyl 4 ethoxy alpha naphthamidine hydrochloride.

RICHARD BALTZLY. EMlIl LORZ.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,049,582 Ziegler Aug. 4, 1936 2,375,611 Barber et al. May 8, 1945 

